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United States Patent |
6,169,920
|
Haak
,   et al.
|
January 2, 2001
|
Iontophoretic drug delivery apparatus
Abstract
An iontophoretic delivery device (10) is provided. Device (10) has an
electronic circuit (32) having electronic components such as batteries
(30) mounted thereon. Device (10) also includes a pair of electrode
assemblies (18, 19). The electronic circuit (32) is electrically connected
to the electrode assemblies (18, 19) using an electrically conductive
adhesive (34). The adhesive can also be used to electrically connect two
or more electronic components within circuit (32) or to connect an
electronic component to the electronic circuit (32). In one practice of
the invention, the electrically conductive adhesive (44) functions as an
electrode and electrically connects the circuit (32) to an
agent-containing reservoir (24, 25). In a further practice of the
invention, the electrically conductive adhesive (93) functions as an agent
reservoir and contains the agent to be iontophoretically delivered.
Inventors:
|
Haak; Ronald P. (San Jose, CA);
Meyers; Robert M. (Stanford, CA);
Landrau; Felix A. (San Jose, CA);
Sanders; Harold F. (La Jolla, CA);
Kleiner; Lothar W. (Los Altos, CA);
Gyory; J. Richard (San Jose, CA)
|
Assignee:
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Alza Corporation (Mountain View, CA)
|
Appl. No.:
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320387 |
Filed:
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October 11, 1994 |
Current U.S. Class: |
604/20; 607/152 |
Intern'l Class: |
A61N 001/30 |
Field of Search: |
128/802,803,798,640
604/20
606/149-152
607/152
|
References Cited
U.S. Patent Documents
3911906 | Oct., 1975 | Reinhold, Jr. | 128/640.
|
4067342 | Jan., 1978 | Burton | 128/798.
|
4141366 | Feb., 1979 | Cross, Jr. et al. | 128/640.
|
4273135 | Jun., 1981 | Larimore et al. | 128/640.
|
4365634 | Dec., 1982 | Bare et al. | 128/640.
|
4679563 | Jul., 1987 | Wada et al. | 607/152.
|
4684558 | Aug., 1987 | Keusch et al. | 428/40.
|
4706680 | Nov., 1987 | Keusch et al. | 128/640.
|
4777954 | Oct., 1988 | Keusch et al. | 128/641.
|
4820263 | Apr., 1989 | Spevak et al. | 604/20.
|
4865582 | Sep., 1989 | Sibalis | 604/20.
|
4874548 | Oct., 1989 | Hajousky | 252/511.
|
4989607 | Feb., 1991 | Keusch et al. | 128/640.
|
5084006 | Jan., 1992 | Lew et al. | 604/20.
|
5087314 | Feb., 1992 | Sandborn et al. | 156/330.
|
5158537 | Oct., 1992 | Haak et al. | 604/20.
|
5176852 | Jan., 1993 | Kondo et al. | 252/510.
|
5240761 | Aug., 1993 | Calhoun et al. | 428/148.
|
Foreign Patent Documents |
174777 | Mar., 1986 | EP.
| |
2170365 | Jul., 1986 | GB.
| |
9009413 | Aug., 1990 | WO.
| |
Other References
Polyurethanes--Durometer Chart.*
|
Primary Examiner: Bockelman; Mark
Attorney, Agent or Firm: Michael Best & Friedrich LLP, Frenchick; Grady J., Meier; Linda Blair
Parent Case Text
CROSS-REFERENCE TO RELATED APPLICATION
This application is a continuation of patent application Ser. No.
07/892,258, filed Jun. 2, 1992, now abandoned, that was concurrently filed
with commonly owned patent application Ser. No. 07/889,950, now U.S. Pat.
No. 5,312,326 entitled "IONTOPHORETIC DRUG DELIVERY APPARATUS." The
disclosure of that concurrently filed patent application is incorporated
by reference herein.
Claims
What is claimed is:
1. An iontophoretic agent delivery device comprising:
a reservoir for containing the agent to be iontophoretically delivered,
said reservoir being adapted to be placed in agent transmitting relation
with a body surface through which said agent is to be delivered;
an electronic circuit, electrically connected to said reservoir, said
circuit having a plurality of electronic components, and including a
source of electrical energy, and having a circuit output, said electronic
circuit being capable of controlling the level of electric current applied
by the device;
a polymeric adhesive means in direct electrical contact with said circuit
output, said adhesive means being electronically conductive and comprising
at least a portion of the electrical connection of the circuit to the
reservoir, said adhesive means being capable of repeated bending, twisting
or deforming so as to permit the reservoir to conform to the body surface
to which the reservoir is adapted to be placed in agent transmitting
relation throughout the normal range of body surface movement and activity
without breakage of the electrical connection.
2. The device of claim 1 wherein the adhesive means adheres to, and
electrically connects, the circuit output and an electrode, which
electrode is in electrical contact with the reservoir.
3. The device of claim 1, wherein the adhesive means adheres to, and
electrically connects, the circuit output and the agent reservoir.
4. The device of claim 3, wherein the adhesive means contains an
electrochemically reactive species.
5. The device of claim 4, wherein the adhesive means comprises an anodic
electrode and the electrochemically reactive species is capable of
undergoing electrochemical oxidation.
6. The device of claim 4, wherein the adhesive means comprises a cathodic
electrode and the electrochemically reactive species is capable of
undergoing electrochemical reduction.
7. The device of claim 1, wherein the adhesive means comprises a conductive
web, mat or mesh and an adhesive matrix.
8. The device of claim 1, wherein the adhesive means comprises an adhesive
matrix containing a conductive filler.
9. The device of claim 8, wherein the adhesive matrix comprises a
hydrophobic polymer and a tackifying resin.
10. The device of claim 8, wherein the adhesive matrix comprises a pressure
sensitive adhesive.
11. The device of claim 8, wherein the adhesive matrix comprises low
molecular weight polyisobutylene and high molecular weight polyisobutylene
in a volume ratio of about 6:1 to about 2:1.
12. The device of claim 8, wherein the filler comprises a conductive
particulate or fibrous material.
13. The device of claim 12, wherein the conductive filler comprises carbon
particles or fibers.
14. The device of 12, wherein the conductive filler comprises metal
particles or flakes.
15. The device of claim 1 wherein the electrically conductive adhesive
means is formed by laminating at least one layer of an adhesive material
to at least one electrically conductive web, mesh or mat.
16. The device of claim 15 wherein the electrically conductive adhesive
means is formed by laminating:
a first adhesive layer, overlying;
an electrically conductive web, mat or mesh.
17. The device of claim 16, wherein the electrically conductive web, mat or
mesh overlies a second adhesive layer.
18. The device of claim 16 wherein the conductive web, mat or mesh is
comprised of carbon fibers.
19. The device of claim 1 wherein the adhesive means has a resistivity of
less than about 1000 ohm-cm.
20. The device of claim 1 wherein the conductive adhesive means comprises
at least a portion of said reservoir.
21. The device of claim 1 wherein the adhesive means contains a liquid
retaining additive.
22. The device of claim 21 wherein the additive comprises a hydrophilic
polymer.
23. An iontophoretic agent delivery device comprising:
a reservoir for containing the agent to be iontophoretically delivered,
said reservoir being adapted to be placed in agent transmitting relation
with a body surface through which said agent is to be delivered;
an electronic circuit electrically connected to said reservoir, said
circuit having a plurality of electronic components, and including a
source of electrical energy, and two circuit outputs, said circuit being
capable of controlling the level of electric current applied by the
device, said circuit being capable of conforming to the contours of the
body surface to which the reservoir is to be placed in agent transmitting
relation;
an anode and a cathode, each of said anode and said cathode being directly
electrically connected to one of said circuit outputs by an electrically
conductive polymeric adhesive means which adheres to said circuit outputs
and said electrodes, in at least a portion thereof, to connect said
circuit outputs to said electrodes, said adhesive means being capable of
repeated bending, twisting or deforming so as to permit the reservoir to
conform to the body surface to which the reservoir is adapted to be placed
in agent transmitting relation throughout the normal range of body surface
movement and activity without breakage of the electrical connection.
24. The device of claim 23 wherein the source of electrical energy
comprises a battery.
25. The device of claim 23 wherein the electrically conductive adhesive is
formed by laminating at least one layer of an adhesive material to at
least one electrically conductive web, mat or mesh.
26. The device of claim 25 wherein the electrically conductive adhesive is
formed by laminating:
a first adhesive layer, overlying;
an electrically conductive web, mat or mesh.
27. The device of claim 26, wherein the electrically conductive web, mat or
mesh overlies a second layer of adhesive.
28. The device of claim 27 wherein the additive is hydrophilic.
29. In an iontophoretic delivery device including a reservoir for
containing the agent to be delivered and an electronic circuit having a
plurality of electronic components, including a source of electrical
energy, and having a circuit output, a method of coupling the circuit
output to an electrode comprising the steps of:
providing an electrode in electrical contact with the reservoir; and
electrically connecting the circuit output to the electrode by applying a
sheet of an electrically conductive, polymeric adhesive to the circuit
output and to the electrode the sheet being capable of repeated bending,
twisting or deforming so as to permit the electrode to remain in contact
with the reservoir.
30. The method of claim 29, wherein the sheet is flexible.
31. The method of claim 29, wherein the electrically conductive adhesive
comprises an adhesive matrix and an electrically conductive filler.
32. The method of claim 31, wherein the adhesive matrix comprises a
hydrophobic polymer and a tackifying resin.
33. The method of claim 31, wherein the adhesive matrix comprises a
pressure sensitive adhesive.
34. The method of claim 31, wherein the adhesive matrix comprises low
molecular weight polyisobutylene and high molecular weight polyisobutylene
in a volume ratio of about 6:1 to about 2:1.
35. The method of claim 31, wherein the filler comprises a conductive
particulate or fibrous material.
36. The method of claim 31, wherein the conductive filler comprises carbon
particles or fibers.
37. The method of claim 31, wherein the conductive filler comprises metal
particles or flakes.
38. The method of claims 29, wherein the adhesive comprises a conductive
web, mat or mesh and an adhesive matrix.
39. The method of claim 29 wherein the electrically conductive adhesive
comprises a laminate of an adhesive material and at least one electrically
conductive web, mesh or mat.
40. The method of claim 39 wherein the electrically conductive adhesive is
formed by laminating:
a first adhesive layer, overlying;
an electrically conductive web, mat or mesh.
41. The method of claim 40, wherein the electrically conductive web, mat or
mesh overlies a second adhesive layer.
42. The method of claim 40 wherein the conductive web, mat or mesh is
comprised of carbon fibers.
43. The method of claim 29 wherein the electrically conductive adhesive has
a resistivity of less than about 1000 ohm-cm.
44. An iontophoretic agent delivery device comprising:
a reservoir for containing the agent to be iontophoretically delivered,
said reservoir being adapted to be placed in agent transmitting relation
with a body surface through which said agent is to be delivered;
an electronic circuit having a plurality of electronic components including
a source of electrical energy, and having a circuit output electrically
connected to the reservoir, said electronic circuit being capable of
controlling the level of electronic current applied by the device; an
electrically conductive polymeric adhesive, in the form of a sheet,
adhering to and electrically connecting at least two of said electronic
components said sheet being capable of repeated bending, twisting or
deforming so as to permit the sheet to remain in contact with said
electronic components.
45. The device of claim 44, wherein the adhesive comprises a conductive
web, mat or mesh and an adhesive matrix.
46. The device of claim 44, wherein the adhesive comprises an adhesive
matrix containing a conductive filler.
47. The device of claim 46, wherein the adhesive matrix comprises a
hydrophobic polymer and a tackifying resin.
48. The device of claim 46, wherein the adhesive matrix comprises a
pressure sensitive adhesive.
49. The device of claim 46, wherein the adhesive matrix comprises low
molecular weight polyisobutylene and high molecular weight polyisobutylene
in a volume ratio of about 6:1 to about 2:1.
50. The device of claim 46, wherein the filler comprises a conductive
particulate or fibrous material.
51. The device of claim 50, wherein the conductive filler comprises carbon
particles or fibers.
52. The device of 50, wherein the conductive filler comprises metal
particles or flakes.
53. The device of claim 44 wherein the electrically conductive adhesive
comprises a laminate of an adhesive material and at least one electrically
conductive web, mesh or mat.
54. The device of claim 53 wherein the electrically conductive adhesive is
formed by laminating:
a first adhesive layer, overlying;
an electrically conductive web, mat or mesh.
55. The device of claim 54, wherein the electrically conductive web, mat or
mesh overlies a second adhesive layer.
56. The device of claim 54 wherein the conductive web, mat or mesh is
comprised of carbon fibers.
57. The device of claim 44 wherein the electrically conductive adhesive has
a resistivity of less than about 1000 ohm-cm.
58. In an iontophoretic delivery device for delivery of an agent through a
body surface, the device being adapted to be placed in agent transmitting
relation with a body surface, said device also being capable of conforming
to the contours of the body surface to which said device is to transmit
agent throughout the normal range of body surface movement and activity,
the device including a reservoir for containing the agent to be delivered
and an electronic circuit having a plurality of electronic components,
including a source of electrical energy, and having a circuit output, a
method of coupling the circuit output to an electrode comprising the steps
of:
providing an electrode in electrical contact with the reservoir; and
electrically connecting the circuit output to the electrode by applying a
sheet of an electrically conductive, polymeric adhesive to the circuit
output and to the electrode, the sheet being capable of repeated bending,
twisting or deforming so as to permit the device to conform to the body
surface to which the device is adapted to be placed in agent transmitting
relation throughout the normal range of body surface movement and activity
without breakage of the electrical connection.
Description
TECHNICAL FIELD
The present invention generally concerns an apparatus for the electrically
assisted delivery of a therapeutic agent. This invention also concerns a
method for making such an apparatus.
More specifically, this invention concerns a flexible apparatus for
iontophoretic drug delivery having at least two components which are
electrically connected in a novel, inexpensive, yet reliable manner.
Preferably, the apparatus has an electronic circuit which is electrically
connected to another component or sub-assembly of the apparatus in this
same novel, inexpensive, yet reliable manner.
BACKGROUND OF THE INVENTION
The present invention concerns apparatuses for transdermal delivery or
transport of therapeutic agents, typically through iontophoresis. Herein
the terms "iontophoresis" and "iontophoretic" are used to refer to methods
and apparatus for transdermal delivery of therapeutic agents, whether
charged or uncharged, by means of an applied electromotive force to an
agent-containing reservoir. The particular therapeutic agent to be
delivered may be completely charged (i.e., 100% ionized), completely
uncharged, or partly charged and partly uncharged. The therapeutic agent
or species may be delivered by electromigration, electroosmosis or a
combination of the two. Electroosmosis has also been referred to as
electrohydrokinesis, electro-convection, and electrically-induced osmosis.
In general, electroosmosis of a therapeutic species into a tissue results
from the migration of solvent, in which the species is contained, as a
result of the application of electromotive force to the therapeutic
species reservoir.
As used herein, the terms "iontophoresis" and "iontophoretic" refer to (1)
the delivery of charged drugs or agents by electromigration, (2) the
delivery of uncharged drugs or agents by the process of electroosmosis,
(3) the delivery of charged drugs or agents by the combined processes of
electromigration and electroosmosis, and/or (4) the delivery of a mixture
of charged and uncharged drugs or agents by the combined processes of
electromigration and electroosmosis.
lontophoretic devices for delivering ionized drugs through the skin have
been known since the early 1900's. Deutsch U.S Pat. No. 410,009 (1934)
describes an iontophoretic device which overcame one of the disadvantages
of such early devices, namely that the patient needed to be immobilized
near a source of electric current. The Deutsch device was powered by a
galvanic cell formed from the electrodes and the material containing the
drug to be transdermally delivered. The galvanic cell produced the current
necessary for iontophoretically delivering the drug. This device allowed
the patient to move around during iontophoretic drug delivery and thus
imposed substantially less interference with the patient's daily
activities.
In presently known iontophoresis devices, at least two electrodes are used.
Both of these electrodes are disposed so as to be in intimate electrical
contact with some portion of the skin of the body. One electrode, called
the active or donor electrode, is the electrode from which the ionic
substance, agent, medicament, drug precursor or drug is delivered into the
body via the skin by iontophoresis. The other electrode, called the
counter or return electrode, serves to close the electrical circuit
through the body. In conjunction with the patient's skin contacted by the
electrodes, the circuit is completed by connection of the electrodes to a
source of electrical energy, e.g.,, a battery. For example, if the ionic
substance to be driven into the body is positively charged, then the
positive electrode (the anode) will be the active electrode and the
negative electrode (the cathode) will serve to complete the circuit. If
the ionic substance to be delivered is negatively charged, then the
cathodic electrode will be the active electrode and the anodic electrode
will be the counter electrode.
Furthermore, existing iontophoresis devices generally require a reservoir
or source of the beneficial agent or drug, preferably an ionized or
ionizable species (or a precursor of such species) which is to be
iontophoretically delivered or introduced into the body. Examples of such
reservoirs or sources include a pouch as described in the previously
mentioned Jacobsen U.S. Pat. No. 4,250,878, a pre-formed gel body as
disclosed in Webster U.S. Pat. No. 4,382,529 and a generally conical or
domed molding of U.S. Pat. No. 4,722,726 to Sanderson et al. Such drug
reservoirs are connected to the anode or the cathode of an iontophoresis
device to provide a fixed or renewable source of one or more desired
species or agents.
Perhaps the most common use of iontophoresis today is in diagnosing cystic
fibrosis by delivering pilocarpine transdermally. Iontophoretically
delivered pilocarpine stimulates sweat production, the sweat is collected,
and is analyzed for its chloride ion content. Chloride ion concentration
in excess of certain limits suggests the possible presence of the disease.
A variety of methods for attaching an iontophoretic delivery device to the
skin of a patient have been disclosed, including straps, adhesive
overlays, and in-line ion-conducting adhesives. For example, Sibalis U.S.
Pat. Nos. 4,557,723; 4,640,789; 4,622,031; 4,708,716; 4,713,050; and
4,878,892 describes transdermal iontophoretic drug applicators having a
return electrode which is secured to the skin with a layer of an
electrically conductive adhesive material (i.e., the layer designated 36
in FIG. 2 of U.S. Pat. No. 4,557,723). None of the above Sibalis patents
disclose a specific composition for the skin-contacting, electrically
conductive adhesive material.
PCT published application WO 90/09413 discloses ion-conducting skin
contacting adhesives for securing iontophoretic drug delivery devices to
the skin. The contact adhesives (eg., silicone adhesives) disclosed
therein have a predominantly hydrophobic character which is modified by
the addition of a hydrophilic, usually polymeric, material to the
hydrophobic adhesive. The hydrophilic additive provides a plurality of
water retaining pathways through the otherwise hydrophobic adhesive
matrix. Drug ions or molecules are transported through the adhesive by way
of these water retaining pathways by electromigration and/or
electroosmosis. Thus, these adhesives can be used as "in-line" adhesive
layers positioned between a drug-containing (donor) reservoir, or a
salt-containing (counter) reservoir, and the skin.
In the devices of these patents, the electrical coupling of the various
electronic components (e.g., resistors, current regulators, pulse
generators, batteries, etc) has been accomplished using conventional
electrical coupling means such as soldered electrical connections.
Unfortunately, soldered electrical connections have a very poor tolerance
for flexing. This is a serious disadvantage in devices such as
iontophoretic drug delivery devices adapted to be worn on the skin for
extended periods of time, e.g., as long as a week or more. When flexible
(i.e., nonrigid) iontophoretic drug delivery devices having conventional
soldered electrical connections are worn for such extended periods of
time, there is a tendency for the electrical connections to break due to
the flexing encountered during the patient's body movements. Breakage of
an electrical connection can render the device completely inoperative.
Another approach described by Sibalis in U.S. Pat. No. 4,856,188 uses a
flexible plastic sheet coated on one side with an electrically conductive
coating to connect a battery of an iontophoresis apparatus to the
electrodes. The opposite side of the sheet has an adhesive coating. The
sheet is folded to permit the conductive coating to contact the battery
terminal and the electrode. This approach tends to produce stress points
at the folds which can cause the conductive coating to crack which can
render the device completely inoperative.
Thus, there has been a need in the art for a means for electrically
connecting or coupling electrical components in a flexible iontophoretic
delivery device, which connections are not susceptible to breaking upon
flexing of the device and which provide good electrical continuity at low
cost.
More recently, there has been an effort to develop miniaturized
iontophoretic drug delivery devices which are adapted to be worn on the
skin unobtrusively under a patient's clothing. The electrical components
in such miniaturized iontophoretic drug delivery devices are also
preferably miniaturized and may be in the form of either microchips or
small printed circuits. While printed circuits are desirable from a cost
standpoint, there have been difficulties encountered in electrically
connecting the printed circuit to the electrode assemblies containing the
agent to be delivered. Specifically, printed electronic circuits are
formed by printing or otherwise depositing electrically conductive
pathways on a flexible substrate, usually in the form of a polymer sheet.
Electronic components, e.g., batteries, resistors, pulse generators,
capacitors etc, are then electrically connected, e.g., by soldering, to
the printed or deposited electrically conductive pathways to form a
complete circuit. Thus, in a typical case, both the printed electrically
conductive pathways, as well as all of the electronic components
electrically connected thereto, are located on one side of the flexible
substrate. Because of the non-uniform height and cross-section presented
by the various electrical components within the completed circuit, there
have been difficulties encountered in laminating drug and/or electrolyte
reservoirs to the side of the flexible circuit having the printed
electrically conducted pathways and the electrical components mounted
thereon.
One solution to this problem is to laminate the drug and electrolyte
reservoirs to the opposite side of the flexible substrate. Unfortunately,
this presents a problem in electrically connecting the drug and
electrolyte reservoirs to the circuit. Thus, there has been a need in the
art for a means for electrically connecting or coupling electrode
assemblies, including drug and electrolyte reservoirs, of an iontophoretic
delivery device to an electronic circuit having electrically conductive
pathways and individual electronic components provided on one surface
thereof, which connections are not susceptible to breaking upon flexing of
the device and which provides good electrical continuity at low cost.
DESCRIPTION OF THE INVENTION
Briefly, in one aspect, the present invention comprises an iontophoretic
drug delivery apparatus or electrotransport system having a flexible,
electrically conductive adhesive means matrix or an electrically conducted
adhesive (ECA) for coupling components of the system. The electrically
conductive adhesive means can be used to couple, electrically, any two or
more electrical components of the system, but preferably is used to couple
an electrical circuit (e.g., a printed circuit) to an electrode assembly.
In a preferred practice, the ECA means is used to couple an electrical
circuit output to an electrode, e.g., an anode or a cathode. As discussed
hereinafter, the electrode may be coupled to further structure, e.g., a
drug or electrolyte reservoir.
In a particularly preferred practice, the ECA means or matrix comprises a
composite which is formed by laminating at least one layer of an adhesive
material to at least one electrically conductive web, mat or mesh. The
lamination takes place under conditions which cause the adhesive material
to flow into the web, mat or mesh, resulting in a composite ECA of
relatively uniform cross-section.
In yet a further practice of this invention, the ECA may itself comprise an
electrode which is used to electrically connect an electrical circuit
output to either (1) a drug reservoir (in the case of a donor electrode
assembly) or (2) an electrolyte salt reservoir (in the case of a counter
electrode assembly). In this practice of the invention it is preferred
that the ECA electrode contain an electrochemically reactive species which
generates or consumes ions during operation of the ECA-electrode. In the
case of an ECA anode, the electrochemically reactive species should be
capable of undergoing electrochemical oxidation during operation of the
ECA anode. In the case of an ECA-cathode, the electrochemically reactive
species should be capable of undergoing electrochemical reduction during
operation of the ECA cathode. In addition, the ECA-electrode should be
ion-conducting as well as electrically conducting (i.e.,
electron-conducting). In order to render the ECA ion-conducting, a liquid
solvent-retaining, usually hydrophilic material, is added to the ECA.
BRIEF DESCRIPTION OF THE DRAWINGS
A better understanding of the present invention as well as other objects
and advantages thereof will become apparent upon consideration of the
following detailed description especially when taken with the accompanying
drawings, wherein like numerals designate like parts throughout, and
wherein:
FIG. 1 is a side sectional view of an iontophoretic delivery device;
FIG. 2 is a top view of the device of FIG. 1;
FIG. 3 is a side sectional view of an alternative device according to this
invention;
FIG. 4 is a side view of an apparatus for making a preferred composite
electronically conductive adhesive material;
FIG. 5 is a top view of an electrical circuit useable in the present
invention;
FIG. 6 is a perspective view of an alternative iontophoretic delivery
device according to this invention.
FIG. 7 is a top view of an apparatus of the invention, illustrating a
preferred ECA shape;
FIG. 8 is a side sectional view of the device of FIG. 7 taken along line
8--8 of FIG. 7; and
FIG. 9 is a side sectional view of another apparatus according to the
present invention.
MODES FOR CARRYING OUT THE INVENTION
FIG. 1 is a schematic depiction of an iontophoretic delivery device 10.
Device 10 can have essentially any convenient size or shape, whether
square, oval, circular, or tailored for a specific location on the body.
Device 10 is flexible and can easily conform to a body (e.g., skin)
surface and flex with normal body movement. Device 10 has an electronic
circuit 32 having batteries 30 mounted thereon. Generally, circuit 32 is
relatively thin and preferably comprised of electronically conductive
pathways printed, painted or otherwise deposited on a thin, flexible
substrate 39 such as, for example, a film or polymeric web, e.g., circuit
32 is a printed flexible circuit. In addition, to the power source 30,
circuit 32 may also include one or more electronic components which
control the level, waveform shape, polarity, timing, etc. of the electric
current applied by device 10. For example, circuit 32 may contain one or
more of the following electronic components: control circuitry such as a
current controller (e.g., a resistor or a transistor-based current control
circuit), an on/off switch, and/or a microprocessor adapted to control the
current output of the power source over time. Circuit 32 has two circuit
outputs 31 and 33, each of which is overlain by a layer 34 of an
electrically conductive adhesive (ECA). Circuit 32 and ECA layers 34 are
preferably covered with a water-impermeable backing layer 21.
The term "flexible" when used herein to describe a device or a component of
a device, means being capable of conforming to the contours of the area of
the body to which the device is attached or to which it most closely
approaches, i.e., to be conformable. "Flexible", as used herein, also
means being capable of repeated bending, twisting, or deforming so as to
continue to conform to the body throughout the normal range of patient
movement and activity. For an entire device to be flexible, generally
speaking, each of its individual components also must be flexible.
Device 10 includes two electrode assemblies indicated by brackets 18 and
19. Electrodes assemblies 18 and 19 are separated from one another by an
electrical insulator 26, and form therewith a single self-contained unit.
For purposes of illustration, the electrode assembly 18 is sometimes
referred to as the "donor" electrode assembly while electrode assembly 19
is sometimes referred to as the "counter" electrode assembly. These
designations of the electrode assemblies are not critical and may be
reversed in any particular device or in operation of the device shown.
In device 10, a donor electrode 22 is positioned adjacent a drug reservoir
24 while a counter electrode 23 is positioned adjacent a return reservoir
25 which contains an electrolyte. Electrodes 22 and 23 may comprise metal
foils, or a polymer matrix loaded with metal powder, powdered graphite,
carbon fibers, or any other suitable electrically conductive material.
Reservoirs 24 and 25 can be polymeric matrices or gel matrices adapted to
hold a liquid solvent. Aqueous-based or polar solvents, especially water,
are generally preferred when delivering agents across biological membranes
such as skin. When using an aqueous-based solvent, the matrix of
reservoirs 24 and 25 is preferably comprised of a water retaining material
and is most preferably comprised of a hydrophilic polymer such as a
hydrogel. Natural or synthetic polymer matrices may be employed.
Insulator 26 is composed of a non-electrical conducting and
non-ion-conducting material which prevents current (i.e., current in the
form of either electrons or ions) from passing directly between electrode
assemblies 18 and 19 thereby short circuiting the body to which the device
is attached. Insulator 26 can be an air gap, a non-ion-conducting polymer
or adhesive, or other suitable barrier to ion and electron flow.
The device 10 can be adhered to the skin by means of optional
ion-conducting adhesive layers 27 and 28. The device 10 also preferably
includes a strippable release liner 29 which is removed just prior to
application of the device to the skin. Alternatively, device 10 can be
adhered to the skin by means of an adhesive overlay of the type which are
conventionally used in transdermal drug delivery devices. Generally
speaking, an adhesive overlay contacts the skin around the perimeter of
the device to maintain contact between reservoirs 24 and 25 and the
patient's skin.
In a typical device 10, the drug reservoir 24 contains a neutral, ionized,
or ionizable supply of the drug or agent to be delivered and the counter
reservoir 25 contains a suitable electrolyte such as, for example, sodium
chloride, potassium chloride, or mixtures thereof. Alternatively, device
10 can contain an ionizable, or neutral supply of drug in both reservoirs
24 and 25 and in that manner both electrode assemblies 18 and 19 would
function as donor electrode assemblies. For example, positive drug ions
could be delivered through the skin from the anode electrode assembly,
while negative drug ions could be introduced from the cathode electrode
assembly. Generally, the combined skin-contacting area of electrode
assemblies 18 and 19 can range from about 1 cm.sup.2 to about 200
cm.sup.2, but typically will range from about 5 cm.sup.2 to about 50
cm.sup.2.
The drug reservoir 24 and return reservoir 25 of the iontophoretic delivery
device 20 must be placed in agent or drug transmitting relation with the
patient so as to iontophoretically deliver agent or drug. Usually this
means the device is placed in intimate contact with the patient's skin.
Various sites on the human body may be selected depending upon the
physician's or the patient's preference, the drug or agent delivery
regimen or other factors such as cosmetic.
FIG. 2 depicts a top view of the rectangularly-shaped, flexible device of
FIG. 1 with the backing layer 21 removed for purposes of illustration. As
shown, batteries 30 are electrically connected to the circuit 32. Circuit
32 has circuit output portions 31 and 33 which are each overlain by ECA
34.
FIG. 5 illustrates one example of a flexible circuit 32 which can be
utilized in the present invention. The circuit of FIG. 5 includes
electrically conductive pathways which are printed or otherwise deposited
on a thin flexible (e.g., polymeric) sheet 39. One or more electrical
components including three button cell batteries 30 are mounted and
connected to the conductive pathways of circuit 32. Circuit 32 also
includes circuit outputs 31 and 33 on which the ECA can be applied in
order to electrically connect the outputs 31 and 33 to the adjacent
(usually underlying) electrode assemblies 18 and 19, respectively.
Generally speaking, the ECA 34 should be electrically conductive. The terms
"electrically conductive" and "conductive" as used herein means having a
bulk resistivity of less than about 1000 ohm-cm, preferably less than
about 100 ohm-cm, and most preferably less than about 1 ohm-cm. The
adhesive should be electrically conductive in all directions, i.e., in a
direction parallel to the major surfaces of ECA 34 as well as in a
direction perpendicular thereto. In order to impart conductivity to an
adhesive, an electrically conductive filler must generally be added to the
adhesive. Examples of suitable electrically conductive fillers include
carbon particles and fibers, metal flakes and powders such as silver, zinc
or gold flakes and powders, conductive compounds such as silver chloride
or silver oxide, or conductively coated polymer particles, e.g., silver
coated polyvinylpyrrolidone particles. Conductive fibers in the form of a
woven mat or web, a non-woven mat or web, or a conductive fabric may also
be employed.
ECA 34 should also be adhesive, i.e., ECA 34 should be capable of adhering
to both circuit 32 and the underlying electrode assembly. Generally
speaking, the term "adhesive", when referring to a material, means that
the material to which the term is applied has greater internal cohesion
than external adhesion. Generally speaking, this means that substantially
none of the adhesive material remains on a surface from which the adhesive
is peeled. Pressure sensitive adhesives are a recognized class of
materials which are "adhesive" as the term is used herein. "Adhesive" also
means capable of causing one material, component, or layer to adhere to
another.
The matrix of ECA 34 is preferably comprised of a polymer. The polymer
itself can have adequate adhesive properties or it may be rendered
suitably adhesive by the addition of tackifying resins. Suitable
hydrophobic polymers include, without limitation, acrylic or methacrylic
resins such as polymers of esters of acrylic or methacrylic acid with
alcohols such as n-butanol, isopentanol, 2-methyl butanol, 1-methyl
butanol, 1-methyl pentanol, 2-methyl pentanol, 3-methyl pentanol, 2-ethyl
butanol, isooctanol, n-decanol, or n-dodecanol, alone or copolymerized
with ethylenically unsaturated monomers such as acrylic acid, methacrylic
acid, acrylamide, methacrylamide, N-alkoxymethyl acrylamides,
N-alkoxymethyl methacrylamides, N-tert. butylacrylamide, itaconic acid,
vinylacetate, N-branched alkyl maleic acids wherein the alkyl group had
10-24 carbon atoms, glycol diacrylates, or mixtures of these. Typical
examples of commercially available acrylate adhesives suitable for use in
this invention are the polyvinylacetate compounds sold by Monsanto Polymer
Products Co. under the name of GELVA, such as GELVA 737 and GELVA 788,
acrylate adhesives sold by the 3M Company such as 3M #9871 and 3M #9872,
and sold by The Kendall Company under the name Kendall A200C-0. Also
suitable are silicone adhesives which are prepared by the reaction of a
linear polydimethylsiloxane fluid with a solvent-soluble, low molecular
weight silicate resin. A typical example of a silicone adhesive suitable
for use in this invention is a medical grade of silicone
pressure-sensitive adhesive commercially available under the trademark DOW
CORNING.RTM.355 Medical Grade Adhesive from Dow Corning Corporation.
Plasticizers may also be added. A typical example is the addition of
silicone medical fluid to the silicone adhesive.
Suitable polymers which can be rendered adhesive by the addition of
tackifying resins include, without limitation, poly(styrene-butadiene) and
poly(styrene-isoprene-styrene) block copolymers, ethylene vinyl acetate
polymers such as those which are described in U.S. Pat. No. 4,144,317,
plasticized or unplasticized polyvinylchloride, and natural or synthetic
rubber, C.sub.2 -C.sub.4 olefins such as polyethylene, polyisoprene,
polyisobutylene and polybutadiene. Examples of suitable tackifying resins
include, without limitation, fully hydrogenated aromatic hydrocarbon
resins, hydrogenated esters and low molecular weight grades of
polyisobutylene. Particularly suitable are tackifiers sold under the
trademarks Staybelite Ester.RTM. #5 and #10, Regal-Rez.RTM. and
Piccota.RTM., all of Hercules, Inc. (Wilmington, Del.).
Although the ECA of the present invention is not limited to any particular
structure or composition, one particularly preferred ECA is formed by
laminating one or more layers 52, 54 of an adhesive material to one or
more electrically conductive webs, mats or meshes 50 to form a composite
ECA 34 as shown in FIG. 4. One particularly useful composite ECA 34 is
formed by laminating between opposing laminating rollers 40 a single
conductive mat or mesh 50 between two adhesive layers 52, 54. Lamination
is conducted at a suitable temperature and pressure to ensure that layers
52 and 54 "flow" into the intersticial spaces between the fibers/strands
of mesh 50 and intimately contact and adhere to the fibers/strands of mesh
50 so that the entire composite ECA 34 is flexible, adhesive, conductive
and has a substantially uniform cross-section. A composite ECA (not shown)
formed by laminating a single adhesive layer 52 to a single conductive
mesh 50 is also suitable. An alternative composite ECA 34 (not shown) can
be formed by laminating two conductive meshes 50 with a single layer 52 of
adhesive sandwiched therebetween.
Mesh 50 is electrically conductive and preferably has a surface resistance
of less than 10 ohms per square. The strands of the fabric may themselves
be composed of an electrically conductive material (e.g., carbon fibers)
or the fibers may be non-conductive (e.g., nylon fibers) which are coated
with electrically conductive material such as graphite, carbon, silver,
silver oxide, aluminum powder, or gold.
A particularly preferred composite ECA is formed by laminating at least one
layer of an intermingled, non-woven, carbon fiber matting and at least one
other layer of an adhesive polyisobutylene matrix. The non-woven carbon
fiber matting can have a weight of about 3 to 70 g/m.sup.2. The carbon
fiber matting comprises about 1 to 10 volume percent, and preferably about
2 to 5 volume percent, of the total volume of the ECA. This ECA is made by
laminating the polyisobutylene (PIB) into the carbon fiber mat so that the
PIB flows therein and becomes intimately admixed therewith. Within the
above limits, various equivalent formulations will become apparent to one
of ordinary skill in this art. The preferred composite ECA may be produced
by laminating the conductive mesh to one layer, or between two layers, of
adhesive matrix. For example, sheet PIB, in rolled form, and kept usable
by wrapping it with two release liners, is unrolled and laminated onto one
or both major surfaces of a non-woven, conductive carbon mesh. In this
manner, an ECA in sheet form, such as that shown in FIG. 4, is produced.
The sheet can then be cut or otherwise processed into suitable lengths,
shapes or configuration(s) for use in an electrotransport device.
Another ECA formulation comprises carbon fibers or carbon powder mixed or
otherwise blended into either a silicone adhesive material or an acrylate
adhesive material. For example, a formulation of 20 to 50 volume per cent
(preferably about 25 to 45 volume per cent) carbon fiber, the remainder of
the composition being the selected acrylate adhesive or silicone adhesive,
provides an ECA which is highly flexible, has very low electrical
resistivity and has reliable electrical continuity. The ECA can be cut or
punched to form suitably sized strips from, e.g., a suitably rolled or
calendared web or sheet of the ECA material.
Another ECA formulation comprises a mixture of high and low molecular
weight polyisobutylene (PIB) intimately admixed with conductive carbon
fibers or particles. Generally speaking, "high molecular weight"
polyisobutylene, as the term is used herein, means polyisobutylene having
a number average molecular weight of greater than about 800,000 and
preferably greater than about 1,200,000. "Low molecular weight"
polyisobutylene means polyisobutylene having a number average molecular
weight in the range of about 10,000 to 50,000, preferably about 20,000 to
40,000. A preferred ratio of low molecular weight polyisobutylene to high
molecular weight polyisobutylene is in the range of about 6:1 to 2:1, and
most preferably about 5:1 to 3:1. As with the silicone/acrylate-based
formulations described above, a formulation comprising about 20 to 50
volume per cent conductive carbon fibers or particles (preferably about 25
to 45 volume per cent carbon fibers or particles), the remainder
comprising the polyisobutylene mixture, has been found particularly
desirable.
Batteries 30 may be electrically connected in series or in parallel to
obtain the desired voltage and/or capacity necessary to obtain the
electrophoretic action with the particular drug or agent. The exact
orientation (i.e., polarity) of batteries 30 depends on whether the drug
of choice is cationic or anionic. Any conventional small battery can be
employed, arranged and connected in series or parallel to obtain the
desired operating voltage and/or capacity. Of course, battery selection
ultimately depends on such factors as the degree of flexibility or
conformability desired, voltage and current density required for a
specific application, and time of discharge.
The ECA described herein can also be used to electrically connect two or
more electrical components (e.g., batteries 30) together or to
electrically connect the battery output terminals to the electrical
circuit. As shown in FIG. 1, ECA strip 37 is used to electrically connect
one battery 30 to the other. In addition, ECA layers 36 are used to
connect batteries 30 to electrical circuit 32.
ECA 34 is illustrated in FIGS. 1 and 2 as a rectangularly-shaped layer,
however, any shape or configuration which adheres to the circuit outputs
31 and 33 and to the electrode assemblies 18 and 19, respectively, may be
used. Lines, regions, frames, or other configurations of ECA can be
employed, depending upon apparatus design. One particularly preferred
shape for an ECA used to electrically connect circuit 32 to an underlying
electrode assembly is illustrated in FIGS. 7-8. Device 70, like device 10,
has two ECA's 74 which are used to electrically connect circuit outputs 31
and 33 to electrode assemblies 18 and 19. ECA's 74 are each in the shape
of a window frame which contacts the underlying electrode assemblies 18
and 19, respectively, along the outer periphery thereof. Each ECA 74 has
an opening 35 which is roughly centered over the top of each of the
underlying electrode assemblies 18 and 19. When using a window frame
shaped ECA 74, the underlying electrode assemblies 18 and 19 can be
manufactured in a substantially non-hydrated condition. A hydrating
liquid, typically water, can be added to the dry state electrode
assemblies 18 and 19 just before use. The hydrating liquid can be applied,
from either an external source or from an on-board liquid releasing means
or container, directly through the openings 35 in the ECA 74. Optionally,
a liquid wicking material (e.g., cotton gauze) can be placed within
openings 35 in order to wick the hydrating liquid evenly across the top
surfaces of dry state electrode assemblies 18 and 19.
An electrotransport system using this feature of the invention is made by
first laminating a polymeric electrode, a drug or salt reservoir, and a
skin contacting adhesive. This laminate is cut to the desired overall
dimensions). An ECAT then is die cut to the shape of a "window frame."
This window frame is laminated to the electrode side of the laminate of
electrode/drug or salt reservoir/skin adhesive, preferably about its
perimeter or periphery. A piece of water wicking fabric cut to the same
size as the inside dimensions of the window frame (i.e., the cut out
portion) is then placed on top of the electrode. A flexible circuit may
then be applied such that proper contact is made between the ECAT of two
such electrode assemblies and the circuit. Finally, a backing is applied
and edge sealed to the ECAT along the edge of the electrodes.
FIG. 6 shows an iontophoretic device 60 which, like device 70 illustrated
in FIGS. 7 and 8, has an ECA which is permeable to a hydrating liquid to
allow hydration of the underlying dry state electrode assemblies 18 and
19. Device 60 has two ECA layers 64 which are formulated to include an
additive which renders layers 64 able to convey a hydrating liquid,
preferably an aqueous hydrating liquid, therethrough. Any additive which
can convey a hydrating liquid through the ECA layers 64 can be used. Since
water is typically the liquid solvent used to conduct iontophoresis, a
preferred class of additives are water absorbent additives, especially
hydrophilic polymers or gels, for imparting water permeability to ECA
layers 64. Most preferred are hydrophilic, water swellable but
substantially water insoluble polymers, such as cross-linked
polyvinylpyrrolidone. Typically, the ECA layers 64 contain from about 5 to
50 volume percent (preferably about 20 to 30 volume percent) of the
hydrophilic polymer. The hydrophilic materials may be particulate or
granular in nature, and preferably are non-ionic. Hydrophilic particles
can be either water soluble or insoluble, but preferably are water
insoluble. These particles function as a hydroattractant material, forming
aqueous liquid conveying pathways through the generally hydrophobic
adhesive. Suitable materials for the hydrophilic particles include,
without limitation, polyacrylamide (PAA), Klucel.RTM., cross-linked
dextran such as Sephadex (Pharmacia Fine Chemicals, AB, Uppsala, Sweden),
polyvinylalcohol (PVA), Waterlock A-180 (Grain Processing Corp.,
Muscatine, Iowa) which is a starch-graft-poly(sodium
acrylate-co-acrylamide) polymer, cellulosic derivatives such as
hydroxypropylmethylcellulose (HPMC), low-substituted
hydroxypropylcellulose (LHPC) and cross-linked Na-carboxymethylcellulose
such as Ac-Di-Sol (FMC Corp., Philadelphia, Pa.), hydrogels such as
polyhydroxyethyl methacrylate (pHEMA) (National Patent Development Corp.),
blends of polyoxyethylene or polyethylene glycols with polyacrylic acid
such as Polyox.RTM. blended with Carbopol.RTM., cross-linked polyvinyl
pyrrolidone (PVP) (GAF Corporation), cholestyramine resins, natural gums
and chitosan. Also suitable are phospholipids such as
L-.alpha.-phosphatidylcholine (Sigma Chemical Company) which has both
hydrophilic and hydrophobic properties. Blending of the hydrophobic,
adhesive component and the hydrophilic, liquid conveying component can be
done mechanically, either in solution or by milling. No polymerization or
chemical alteration takes place. The resulting adhesive films are then
prepared by extrusion and calendering, or by solvent casting, or by melt
processing.
The addition of the liquid conveying additive allows transport of a liquid
solvent (e.g., water) into and through the ECA layers 64. This enables
device 60 to be manufactured in a substantially dry state, i.e.,
reservoirs 24 and 25 and adhesive layers 27 and 28 are manufactured and
packaged in a substantially dehydrated condition. Manufacture and assembly
of device components in a dehydrated state tends to improve the shelf life
of a device containing a hydration-sensitive drug within reservoir 24
and/or 25. Of course, in order for device 60 to become operational, a
liquid solvent such as water must be added to the ion-conducting portions
of the device (e.g., reservoirs 24 and 25 and skin-contacting adhesive
layers 27 and 28). The presence of a liquid solvent allows drug and/or
other ions to migrate through the ion-conducting portions of device 60
under the influence of an electric field imposed by batteries 30. The dry
adhesive layers 27 and 28 and the dry reservoirs 24 and 25 can be hydrated
immediately before use by adding a liquid solvent (e.g., water) from
either an external source or from an on-board liquid-releasing container
(not shown) directly onto the top surface of ECA layers 64. The liquid is
quickly conveyed through the ECA layers 64, as well as through the
electrode layers 22 and 23 which are formulated to contain the same or
similar water-conveying additive, and absorbed by the dry underlying
layers 24, 25, 27 and 28 due to the presence of the hydrophilic water
conveying additive.
In another practice of this invention, the ECA itself acts as an electrode,
i.e., either as an anode or as a cathode. In this embodiment, the ECA
preferably contains a material which is electrochemically reactive. In
this practice, the ECA is used to electrically connect an electrical
circuit to either a drug containing reservoir (in the case of a donor
electrode assembly) or to a salt-containing reservoir (in the case of a
counter electrode assembly). One example of an iontophoretic delivery
device utilizing ECA electrodes 44 is illustrated in FIG. 3. As shown, ECA
electrodes 44 electrically connect circuit outputs 31 and 33 to drug
reservoir 24 and salt reservoir 25, respectively.
When the ECA electrode 44 is an anode, the electrochemically reactive
material is capable of undergoing an electrochemical oxidation reaction.
When the ECA electrode 44 is a cathode, the electrochemically reactive
material is capable of undergoing an electrochemical reduction reaction.
Examples of preferred oxidation/reduction reactions include the following:
Ag.revreaction.Ag.sup.+ +e.sup.-
Zn.revreaction.Zn.sup.+2 +2e.sup.-
Cu.revreaction.Cu.sup.+2 +2e.sup.-
Ag+Cl .sup.-.revreaction.AgCl+e.sup.-
Zn+2Cl.sup.-.revreaction.ZnCl.sub.2 +2e.sup.-
where the forward reaction is the oxidation reaction taking place at the
anodic electrode and the reverse reaction is the reduction reaction taking
place at the cathodic electrode. Other standard electrochemical reactions
and their respective reduction potentials are well known in the art. See
the CRC Handbook of Chemistry and Physics, pp D 151-158, 67th edition
(1986-1987).
If the ECA electrode is to be used as an anode, the chemical species added
to the ECA should be able to undergo oxidation during operation of the
device. Suitable chemical species able to undergo oxidation include metals
such as silver, zinc, copper, nickel, tin, lead, iron, chromium and other
oxidizable species listed in the CRC Handbook of Chemistry and Physics,
57th edition, D-141 to D-146. Preferred chemical species able to undergo
oxidation are metals, preferably in the form of powders. Most preferred
are silver and zinc powders.
If the ECA electrode is to be used as a cathode, the chemical species added
to the ECA should be able to undergo reduction during operation of the
device. Suitable chemical species which are able to undergo reduction
include silver chloride, silver bromide, silver hexacyanoferrate, and
other reducible species listed in the CRC Handbook of Chemistry and
Physics, 57th edition, D-141 to D146. Of these, silver chloride powder is
most preferred.
Preferably, the matrix of ECA electrodes 44 contains about 5 to 40 vol %,
more preferably about 15 to 30 vol %, and most preferably about 20 to 25
vol % of the electrochemically reactive species.
In another practice of this invention, the ECA acts as a combined electrode
(i.e., an anode or a cathode) and agent-containing reservoir (i.e., a drug
reservoir in the case of a donor electrode or a salt reservoir in the case
of a counter electrode). In this practice, the ECA contains the agent to
be iontophoretically delivered. One example of a device configuration is
illustrated in FIG. 9. In iontophoretic delivery device 90 illustrated in
FIG. 9, the ECA layers 92 and 93 perform several functions. First, one of
ECA layers 92 and 93 contains the drug to be delivered while the other
contains an electrolyte salt. Thus, ECA layers 92 and 93 act as drug
(donor) and salt (counter) reservoirs. Second, ECA layers 92 and 93 act as
electrodes (i.e., anode and cathode) as well. Thus, one of the ECA layers
92 and 93 preferably contains an electrochemically oxidizable species
(e.g., silver) while the other contains an electrochemically reducible
species (e.g., silver chloride). Third, ECA layers 92 and 93 directly
contact the skin and therefore act as a means for securing device 90 to
the skin. Fourth, ECA layers 92 and 93 each form an electrical connection
to circuit 32. Since the ECA layers perform both the functions of drug or
salt reservoir and skin-contacting adhesive, each of ECA layers 92 and 93
must have a liquid solvent retaining additive of the type described in
connection with ECA 64 (FIG. 6) in order to form liquid solvent
(preferably aqueous solvent) pathways through the ECA matrix in order to
allow ions (e.g., drug or electrolyte ions) to flow therethrough under the
influence of an electrical field provided by the batteries 30.
The ECA layers 92 and 93 can be either in a dry or hydrated state when
applied to the biological interface, depending upon the delivery profile
desired or depending upon the stability of the other constituents, for
example, the drug or the oxidizable or reducible species, when water is
present. Utilizing the ECA layers 92 and 93 in a hydrated state may
facilitate the onset of drug delivery as pathways for drug passage will be
immediately available. Hydration of the ECA layers 92 and 93 can be
accomplished in several ways. The ECA layers 92 and 93 can be hydrated
before packaging it in or with the rest of the system. Alternately, the
ECA layers 92 and 93 can be hydrated immediately prior to placement on the
biological interface. Alternately, the aqueous source can be incorporated
into the iontophoretic drug delivery system with a barrier separating the
aqueous source from the ECA layers 92 or 93. At an appropriate time, e.g.,
immediately prior to use, the barrier is broken or removed so as to
hydrate the ECA layers 92 or 93.
To function as a drug or electrolyte salt reservoir, the ECA must contain
agent in an amount sufficient to maintain therapeutic delivery for an
extended period of time. The ECA may also have other additives present
such as are commonly known in the art. These include, plasticizers which
may modify the tack and cohesive strength of the adhesive, fillers which
may reduce the cost and improve handling, and antioxidants which improve
the adhesive's resistance to oxidative degradation.
The terms "agent" or "drug" are used extensively herein. As used herein,
the expressions "agent" and "drug" are used interchangeably and are
intended to have their broadest interpretation as any therapeutically
active substance which is delivered to a living organism to produce a
desired, usually beneficial, effect. In general, this includes therapeutic
agents in all of the major therapeutic areas including, but not limited
to, anti-infectives such as antibiotics and antiviral agents, analgesics
and analgesic combinations, anesthetics, anorexics, antiarthritics,
antiasthmatic agents, anticonvulsants, antidepressants, antidiabetic
agents, antidiarrheals, antihistamines, anti-inflammatory agents,
antimigraine preparations, antimotion sickness preparations,
antinauseants, antineoplastics, antiparkinsonism drugs, antipruritics,
antipsychotics, antipyretics, antispasmodics, including gastrointestinal
and urinary, antispasmodics, anticholinergics, sympathomimetrics, xanthine
derivatives, cardiovascular preparations including calcium channel
blockers, beta-blockers, antiarrythmics, antihypertensives, diuretics,
vasodilators, including general, coronary, peripheral and cerebral,
central nervous system stimulants, cough and cold preparations,
decongestants, diagnostics, hormones, hypnotics, immunosuppressives,
muscle relaxants, parasympatholytics, parasympathomimetrics, proteins,
peptides, polypeptides and other macromolecules, psychostimulants,
sedatives and tranquilizers.
The present invention can be used to iontophoretically deliver the
following drugs: .alpha.-2b interferon, alfentanyl, amphotericin B,
angiopeptin, baclofen, beclomethasone, betamethasone, bisphosphonates,
bromocriptine, buserelin, buspirone, calcitonin, ciclopirox olamine,
copper, cromolyn sodium, desmopressin, diclofenac diflorasone, diltiazem,
dobutamine, dopamine agonists, dopamine agonists, doxazosin, droperidol,
enalaprilat fentanyl, encainide G-CSF, GM-CSF, M-CSF, GHRF, GHRH,
gonadorelin, goserelin, granisetron, haloperidol, hydrocortisone,
indomethacin insulin, insulinotropin, interleukin, isosorbide dinitrate,
ketoprofen, ketoprofen, ketorolac, leuprolide, LHRH, lidocaine,
lisinopril, LMW heparin, melatonin, methotrexate, metoclopramide,
miconazole, midazolam, nafarelin, nicardipine, NMDA antagonists,
octreotide, ondansetron oxybutynin, PGE.sub.1, piroxicam, pramipexole,
prazosin, prednisolone, prostaglandins, scopolamine, seglitide,
sufentanil, terbutaline, testosterone, tetracaine, tropisetron,
vapreotide, vasopressin, verapamil, warfarin, zacopride, zinc, zotasetron.
This invention is also believed to be useful in the iontophoretic delivery
of peptides, polypeptides and other macromolecules typically having a
molecular weight of at least about 300 daltons, and typically a molecular
weight in the range of about 300 to 40,000 daltons. Specific examples of
peptides and proteins in this size range include, without limitation,
LHRH, LHRH analogs such as buserelin, gonadorelin, naphrelin and
leuprolide, GHRH, insulin, heparin, calcitonin, endorphin, TRH, NT-36
(chemical name:
N=[[(s)-4-oxo-2-azetidinyl]carbonyl]-L-histidyl-L-prolinamide), liprecin,
pituitary hormones (e.g., HGH, HMG, HCG, desmopressin acetate, etc,),
follicle luteoids, .alpha.ANF, growth hormone releasing factor (GHRF),
BMSH, TGF-.beta., somatostatin, atrial natriuretic peptide, bradykinin,
somatotropin, platelet-derived growth factor, asparaginase, bleomycin
sulfate, chymopapain, cholecystokinin, chorionic gonadotropin,
corticotropin (ACTH), epidermal growth factor, erythropoietin,
epoprostenol (platelet aggregation inhibitor), follicle stimulating
hormone, glucagon, hirulogs, hyaluronidase, interferon, insulin-like
growth factors, interleukin-2, menotropins (urofollitropin (FSH) and LH),
oxytocin, streptokinase, tissue plasminogen activator, urokinase,
vasopressin, ACTH analogs, ANP, ANP clearance inhibitors, angiotensin II
antagonists, antidiuretic hormone agonists, antidiuretic hormone
antagonists, bradykinin antagonists, CD4, ceredase, CSF's, enkephalins,
FAB fragments, IgE peptide suppressors, IGF-1, neuropeptide Y,
neurotrophic factors, opiate peptides, parathyroid hormone and agonists,
parathyroid hormone antagonists, prostaglandin antagonists, pentigetide,
protein C, protein S, ramoplanin, renin inhibitors, thymosin alpha-1,
thrombolytics, TNF, vaccines, vasopressin antagonist analogs, alpha-1
anti-trypsin (recombinant).
Generally speaking, it is most preferable to use a water soluble form of
the drug or agent to be delivered. Drug or agent precursors, i.e., species
which generate the selected species by physical or chemical processes such
as ionization, dissociation, or dissolution, are within the definition of
"agent" or "drug" herein. "Drug" or "agent" is to be understood to include
charged and uncharged species as described above.
EXAMPLE 1
An iontophoretic drug delivery device having the same configuration as the
device illustrated in FIG. 6 is comprised of the following materials. ECA
layers 64 each comprise 73 volume percent of a mixed polyisobutylene
matrix (4 parts by volume of a low molecular weight PIB, and 1 part by
volume of a high molecular weight PIB, as defined above) and 2 volume
percent of a non-woven, carbon fiber mat. ECA layers 64 each also contain
25 volume percent of a water-conveying polymeric additive, namely,
Polyplasdone XL, a cross-linked polyvinylpyrrolidone having a molecular
weight in excess of 1,000,000. Thus ECA layers 64, in addition to being
electrically conductive, are also water-conveying and thereby permit water
applied to the top surfaces of ECA layers 64 to permeate therethrough to
any underlying hydrophilic layers (e.g., reservoirs 24 and 25 and adhesive
layers 27 and 28) and thereby, act as water wicking layers. ECA layers 64
are each adhered to an output of the circuit 32. Thus, one ECA layer 64
electrically connects circuit 32 to electrode 22 and the other ECA layer
64 electrically connects circuit 32 to electrode 23. In this example,
electrode 22 is an anode, which is connected to the positive terminals of
batteries 30. Electrode 23 is a cathode which is connected to the negative
terminals of batteries 30.
Each of anode 22 and cathode 23 comprise a matrix of 55 volume percent of a
1:1 mixture of low and high molecular weight polyisobutylene and about 20
volume percent of cross-linked polyvinylpyrrolidone. In addition, anode 22
further includes about 25 volume percent silver powder while cathode 23
contains about 25 volume percent AgCl powder. An ion-impermeable and
electrically insulating layer 26 comprised of ethylenevinylacetate, is
interposed between electrode assemblies 18 and 19. Beneath and in intimate
contact with anode 22 is drug reservoir 24. Drug reservoir 24 comprises 40
wt % of a 1:1 mixture of high and low molecular weight polyisobutylene, 35
wt % of metoclopramide HCl, a water soluble drug salt, and 25 wt %
cross-linked polyvinylpyrrolidone.
In intimate, contact with and beneath cathode 23 is salt reservoir 25. Salt
reservoir 25 comprises 40 wt % of a 1:1 mixture of low and high molecular
weight polyisobutylene (PIB), 30 wt % of NaCl, 25 wt % cross-linked
polyvinylpyrrolidone and 5 wt % of a buffering agent. Skin contacting
adhesive layers 27 and 28 are each comprised of about 70 volume percent of
a 4:1 mixture of low and high molecular weight PIB and 30 volume percent
of cross-linked polyvinylpyrrolidone.
The above disclosure will suggest many alternatives, permutations, and
variations of the invention to one of skill in this art. This disclosure
is intended to be illustrative and not exhaustive. All such, permutations,
variations and alternative suggested by the above disclosure are to be
included within the scope of the attached claims.
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